Oxidative halogenation of aromatic compound

ABSTRACT

A process for the halogenation of an aromatic compound wherein the aromatic compound is admixed with a halogenating agent in the presence of an ionic liquid is described. The method for the halogenation of aromatic compounds is preferably halide, sulfur or nitrate ionic liquids has significant advantages over conventional halogenation reactions. These are that the reaction starts with e.g. a halide salt rather than e.g. the halogen, and is therefore more convenient and safer. Also, when the reaction is performed in a nitrate ionic liquid, the only by-product is water.

[0001] The present invention relates to a process for halogenation of aromatic compounds.

[0002] The halogenation of aromatic compounds can be achieved by a number of classical methods. This involves the reaction of an aromatic compound with a halogen^([1]) in the presence of a Lewis acid^([1]). Other methods include use of hypohalous acid,^([2]) N-chloro^([3]) and N-bromo amides,^([1]), dibromoisocyanuric acid in H₂SO₄,^([4]) Cl₂O in H₂SO₄,^([5]) and metal halides such as iron(III) chloride.^([6]) In the early 1960s it was found that the interaction of a halide salt with nitric acid resulted in oxidative halogenation,^([7]) where HNO₃ oxidised a halide ion prior to the reaction with an aromatic compound.^([8]) The reduced nitrous acid formed is unstable and is oxidised back to nitric acid by air.^([9])

[0003] According to one aspect of the present invention, there is provided a process for the halogenation of an aromatic compound wherein the aromatic compound is admixed with a halogenating agent in the presence of an ionic liquid.

[0004] The method for the halogenation of aromatic compounds in preferably halide, sulfur or nitrate ionic liquids has significant advantages over conventional halogenation reactions. These are that the reaction starts with e.g. a halide salt rather than e.g. the halogen, and is therefore more convenient and safer. Also, when the reaction is performed in a nitrate ionic liquid, the only by-product is water.

[0005] The ionic liquid can act as a catalyst for the reaction and can re recycled and reused. This is outlined in Scheme 1.

[0006] Ionic liquids consist of two components, which are a positively charged cation and a negatively charged anion. Generally, any compound that meets the criteria of being a salt (consisting of an anion and cation) and is fluid at or near the reaction temperature or exists in a fluid state during any stage of the reaction may be defined as an ionic liquid.

[0007] The cation for the present process is preferably a 1-alkylpyridinium cation such as 1-hexylpyridinium. Other cations for this process are alkyl- or poly-alkylpyridium, phosphonium, alkyl- or polyalkylphosphonium, imidazolium, alkyl- or polyalkylimidazolium, ammonium, alkyl- or polyalkylammonium, alkyl- or polyalkylpyrrazolium, alkyloxonium or alkylsulfonium cations.

[0008] The anion for the present process is preferably a halide (chloride, bromide or iodide) or a nitrate. Other halide or nitrogen containing anions are also suitable. Other anions include alkylsulfate, such as methanesulfonate, trifluoromethanesulfonate, and hydrogensulfate. Non sulfur-containing anions include those based on nitrogen, phosphorus, boron, silicon, selenium, tellurium, halogens, oxoanions of metals, and antimony, and bismuth based.

[0009] More than one ionic liquid or any combination of ionic liquids may be used. Suitable Process Conditions Temperature ideally 20-80° C. but to include −40° C. to 200° C. Pressure: ideally, atmospheric, but include 1 mbar to 100 bar Time: ideally 1 to 48 hours, can be 1 minute to 1 month.

[0010] Room temperature ionic liquids have been used to great effect as solvents for a number of reactions,^([10]) for example Friedel-Crafts reactions,^([11]) isomerisations of fatty acid derivatives,^([12]) dimerisation reactions of alkenes,^([13]) Diels-Alder reactions^([14]) and hydrogenation reactions.^([15])

[0011] Room temperature ionic liquids such as [emim]Cl—AlCl₃ (X=0.67) ([emim]⁺=1-methyl-3-ethylimidazolium cation), have been found to been used for many reactions,^([16]) although chloroaluminate(III) are moisture sensitive.

[0012] Preferably, the present invention uses water stable ionic liquids as media for the reaction.

[0013] The halogenation reactions of aromatic compounds using concentrated nitrating agent, e.g. nitric acid in combination with a halide salt (ionic liquid) were found to be successful. In addition, the reaction of hydrohalic acid with an aromatic compound in a nitrate ionic liquid was found to halogenate aromatic compounds in a similar manner. The results of the halogenation of benzene, toluene, naphthalene and anisole by the reaction of a halide ionic liquid (molten salt) and nitric acid are shown in Table 1. TABLE 1 The nitration of aromatic compounds with HNO₃, in ionic liquids. Aromatic Ionic Eq. 68% Temp/ Time/ Compound Liquid HNO₃ ° C. h. Product(s) % Yield Benzene [C₁₀mim] Cl 3 80 120 C₆H₅—Cl 99 Toluene [C₁₀mim] Cl 2.5 110 120 2—Cl—C₆H₄—CH₃ 62 4—Cl—C₆H₄—CH₃ 37 Toluene [C₁₂mim] Br 3 110 72 2—Br—C₆H₄—CH₃ 39 4—Br—C₆H₄—CH₃ 60 Anisole [C₁₀mim] Cl 3.3 20 72 2—Cl—C₆H₄—OCH₃ 20 4—Cl—C₆H₄—OCH₃ 79 Anisole [C₁₂mim] Br 2 50 1 4—Br—C₆H₄—OCH₃ 99 Anisole [Bu₄N] I 3 100 24 4—I—C₆H₄—OCH₃ 97 Naphthalene [C₁₂mim] Br 2 50 2 1—Br—C₁₀H₇ 98

[0014] The results of the halogenation of toluene and anisole by the reaction of a hydrohalic acid and nitrate ionic liquid as shown in Table 2. TABLE 2 The nitration of aromatic compounds with 1-butyl-3-methylimidazolium nitrate, in ionic liquids. Aromatic Compound Acid Temp./° C. Time/h. Product(s) % Yield Toluene 38% HCl 100 96 2—Cl—C₆H₄—CH₃ 60 4—Cl—C₆H₄—CH₃ 39 Toluene 49% HBr 100 96 2—Br—C₆H₄—CH₃ 49 4—Br—C₆H₄—CH₃ 50 Toluene 47% HI 100 84 2—I—C₆H₄—CH₃ 0 4—I—C₆H₄—CH₃ 0 Anisole 38% HCl 100 72 2—Cl—PhOCH₃ 20 4—Cl—PhOCH₃ 79 Anisole 49% HBr 80 18 4—Br—PhOCH₃ 99

[0015] The following is a proposed mechanism for the nitration of aromatic in ionic liquids

[0016] (1) H−X+[NO₃]⁻+3H⁺

HNO₃+X⁻ +3H ⁺→HNO₂+“X⁺”+H₂O

[0017] (3) 3HNO₂→2NO+HNO₃+H₂O

[0018] (4) 2NO+O₂→2NO₂

[0019] (5) NO₂+H₂O→HNO₂+HNO₃

[0020] Overall Ar−H+H−X+0.5O₂=Ar−X+H₂O

[0021] The products of these reactions can be isolated in three separate ways. Vacuum distillation allows the products to be separated from this ionic liquid, which leaves the ionic liquid dried and ready for reuse, however, this cannot be used for the separation of high molecular weight products from the ionic liquid because of the high temperatures involved. Solvent extraction with cyclohexane or diethyl ether can be used to isolate most organic products from the reaction, and the ionic liquid then regenerated by distilling off water/unreacted hydrohalic or nitric acids. The third and most successful approach is the use of steam distillation. Complete separation of the organic products from the ionic liquid can be achieved by the addition of water, followed by distillation at 120-140° C. at atmospheric pressure. The product can then be separated from the residual nitric acid usually by phase separation.

[0022] In conclusion, halogenation in ionic liquids using concentrated (68%) nitric acid and a halide salt proceeds efficiently to give the mono-halogenated product in excellent yield. The ionic liquids could all be reused in further halogenation reactions and were not destroyed, despite being in contact with acids under reflux. Separation of the products was achieved by vacuum distillation, solvent extraction, or most notably, steam distillation. The only waste from these reactions is diluted acid, which can be concentrated and recycled.

EXAMPLE

[0023] In a round-bottomed flask (25 cm³) equipped with a magnetic stirrer flea and reflux condensed, 1-butyl-3-methylimidazolium nitrate (1.00 g, 5 mmol) and toluene (0.91 g, 10 mmol) were added. 38% aqueous hydrochloric acid (2.88 g, 30 mmol) was cautiously added and the mixture heated under reflux for 96 hours. The flask was cooled and the products analysed by gas chromatography. All of the toluene had reacted and peaks due to 2- and 4-chlorotoluene (60% and 38% respectively) were observed. The products were isolated by addition of water (5 cm³) distillation at 150° C. This gave 2-phase mixture of dilute hydrochloric acid and chlorotoluene. After phase separation, the structures were confirmed by NMR analysis and were in accordance with authentic material.

[0024] The present invention also extends to the use of an ionic liquid in the halogenation of aromatic compound, as well as a halo- or polyhaloaromatic compound whenever prepared by a process of the invention.

References

[0025]^([1]) De la Mare, Electrophilic Halogenation, Cambridge University Press, Cambridge, 1976.

[0026]^([2]) Nwaukwa, Keehn, Syn. Comm., 1989, 19, 799.

[0027]^([3]) Kajigaeshi, Moriwaki, Tanaka, Fujisaki, Kakinami, Okamoto, J. Chem. Soc., Perkin Trans. 1, 1990, 897.

[0028]^([4]) Gottardi, Monatsh. Chem., 1968, 99, 815.

[0029]^([5]) Marsh, Farnham, Sam, Smart, J. Am. Chem. Soc., 1982, 104, 4680.

[0030]^([6]) Kovacic, Wu, Stewart, J. Am. Chem. Soc., 1960, 82, 1917.

[0031]^([7]) Bergwerksverband G.m.b.H., British patent, GB9175721, 1960.

[0032]^([8]) V. A. Notaro, C. M. Selwitz, U.S. Pat. No. 3,636,170, 1972.

[0033]^([9]) D. I. Makhonkov, A. V. Cheprakov, M. A. Rodkin, I. P. Beletskaya, Zhur. Org. Khim. 1988, 24, 241-248.

[0034]^([10]) M. J. Earle and K. R. Seddon, Pure and App. Chem. 2000, in press.

[0035]^([11]) C. J. ^(Adams), M. J. Earle, G. Roberts and K. R. Seddon. Chem. Commun. 1998, 2097-2098.

[0036]^([12]) C. J . Adams, M. J. Earle, J. Hamill, C. Lok, G. Roberts and K. R. Seddon, World Patent WO 98 07679, 1998.

[0037]^([13]) (a) B. Ellis, W. Keim and P. Wasserscheid, Chem. Commun. 1999, 337. (b) S. Einloft, H. Olivier and Y. Chauvin, U.S. Pat. No. 5,550,306, 1996.

[0038]^([14]) M. J. Earle, P. B. McCormac and K. R. Seddon, Green Chem. 1999, 1 23-25.

[0039]^([15]) (a) T. Fisher, A. Sethi, T. Welton, J. Woolf, Tetrahedron Lett. 1999, 40, 793-194. (b) C. J. Adams, M. J. Earle, K. R. Seddon, Chem. Commun. 1999, 1043-1044.

[0040]^([16 ]) T. Welton. Chem. Rev. 1999, 99, 2071-2083. 

1. A process for the halogenation of an aromatic compound wherein the aromatic compound is admixed with a halogenating agent in the presence of an ionic liquid.
 2. A process as claimed in claim 1 wherein the cation of the ionic liquid is one or more of the group comprising: 1-alkylpyridinium, alkyl- or poly-alkylpyridium, phosphonium, alkyl- or polyalkylphosphonium, imidazolium, alkyl- or polyalkylimidazolium, ammonium, alkyl- or polyalkylammonium, alkyl- or polyalkylpyrrazolium, alkyloxonium or alkylsulfonium.
 3. A process as claimed in claim 2 wherein the cation is 1-hexylpyridinium.
 4. A process as claimed in any one of the preceding claims wherein the anion of the ionic liquid is one or more of the group comprising: a halide (chloride, bromide or iodide) or a nitrate, another halide or nitrogen containing anions, an alkylsulfate, such as methanesulfonate, trifluoromethanesulfonate, and hydrogensulfate, non sulfur-containing anions including those based on nitrogen, phosphorus, boron, silicon, selenium, tellurium, halogens, oxoanions of metals, and anions that are antimony and bismuth-based.
 5. A process as claimed in claim 4 wherein the anion is chloride, bromide, iodide or a nitrate.
 6. A process as claimed in any one of the preceding claims wherein more than one ionic liquid or any combination of ionic liquids may be used.
 7. A process as claimed in any one of the preceding claims wherein the ionic liquid is a water stable ionic liquid.
 8. A process as claimed in any one of the preceding claims wherein the ionic liquid is one of more of the group comprising: [emim]Cl—AlCl₃, [C₁₀mim] Cl, [C₁₂mim] Br, [Bu₄N] I, and 1-butyl-3-methylimidazolium nitrate.
 9. A process as claimed in any one of the preceding claims wherein the hydrogenating agent is one or more of the group comprising: a nitrating agent and a hydrohalic acid.
 10. A process as claimed in claim 9 wherein the nitrating agent is nitric acid.
 11. A process as claimed in any one of the preceding claims wherein the halogenating agent is nitric acid and the ionic liquid is a halide salt.
 12. A process as claimed in any one of the preceding claims wherein the reaction products can be isolated by one or more of the following processes comprising: vacuum distillation, solvent extraction and steam distillation.
 13. A process as claimed in any one of the preceding claims wherein the aromatic compound is benzene, toluene, biphenyl or anisole.
 14. Use of an ionic liquid in a process as claimed in any one of claims 1 to
 13. 15. A halogenated aromatic compound obtainable by a process as defined in any one of claims 1 to
 13. 16. A compound as claimed in claim 15 wherein the aromatic starting compound is benzene, toluene, biphenyl or anisole.
 17. A process for the halogenation of an aromatic compound substantially as hereinbefore described and with reference to the Examples. 